The four named storms in the Atlantic come as one in the Pacific is hitting Hawaii.
Flash floods and storm surges - in some cases up to 13 feet high - are expected to send water gushing over miles of vulnerable coastal areas and river banks further inland.
Horry County Police Chief Joseph Hill urges residents to take the category 4 hurricane seriously.
The eastbound lanes of several major highways have been shut down to allow traffic to flow inland, but the exodus was slow along roads jammed with outward-bound vehicles.
Hurricane Florence, now a Category 4, is on track to hit the U.S. East Coast early Thursday.
Tropical Storm Isaac was expected to pass south of Puerto Rico, Haiti, the Dominican Republic and Cuba, while Hurricane Helene was moving northward away from land.
"They haven't seen anything like what's coming at us in 25-30 years, maybe ever", President Trump said while appearing with FEMA officials in the Oval Office on Tuesday.
"We will handle it".
According to the latest models, the coastal areas of Charleston and Berkeley counties have the highest risk in the Lowcountry region for risky winds that could destroy trees, structures and create massive power outages.
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The center also says the storm could become more powerful. In addition to giving residents enough time to make it out, North and SC have enacted emergency price-gouging laws to keep business and gas stations from upping their prices in the lead-up to Florence's arrival.
Predictions now have the storm stalling and making a slight southward turn after it makes landfall.
Cooper said the coastal region should prepare for life-threatening storm surge and wind, the central part of the state can expect heavy rains and wind, and western North Carolina should be prepared for heavy rains and related issues, like mudslides. Charleston International Airport in SC tweeted that it expected to close runways by midnight Wednesday.
"I'll leave if the winds are still above 130 miles per hour, because my house hasn't been built to resist more", he said.
Mayor Joe Benson of Carolina Beach, a small town near Wilmington with a permanent population of about 6,300, said he believes half of the residents have stayed on the island.
"I will enjoy the quiet", he said.
Florence is headed for a region with some of the most well-known military bases in the country, including Camp Lejeune in North Carolina, Naval Station Norfolk in Virginia and the Marine Corps Recruit Depot on Parris Island in SC.
Gov. Henry McMaster has ordered evacuations in counties along the state's coast, including Charleston.
By late Wednesday, authorities in North Carolina reported almost 7,000 evacuees staying in 71 emergency shelters throughout the state.